The majority of patients with advanced breast cancer develop bone metastases causing considerable morbidity and mortality. Thus, there is a tremendous need to develop novel approaches to treat breast cancer, and is one of the missions of National Cancer Institute. The goal of this proposal is to develop a therapeutic approach that will destroy the primary tumor, and simultaneously inhibit the breast cancer-associated bone metastasis. We will target the transforming growth factor-? (TGF?) pathway because high levels of TGF? protein are known to contribute to the tumor progression, and are associated with bone metastasis in breast cancer patients. We will test whether oncolytic adenoviral vectors (dl01/07 based) expressing the soluble form of TGF? receptor II fused with human Fc lgG1 (Fc) (sTGF?RIIFc) have anti- tumor effects. We constructed a dl01/07 based adenoviral vector expressing sTGF?RIIFc (Ad.sT?RFc). To further restrict viral replication in breast tumor cells, we have constructed mhTERTAd.sT?RFc, a modified 01/07 based adenoviral vector expressing sTGF?RIIFc gene, in which viral replication is under the control of a modified human telomerase reverse transcriptase (mhTERT) promoter. We will test the hypothesis that Ad.sT?RFc and mhTERTAd.sT?RFc will be oncolytic to the tumor cells, will produce sTGF?RIIFc, and will cause minimum or no toxicity to the normal cells. We will also test the hypothesis that adenoviral-mediated production of sTGF?RIIFc will abolish the effects of TGF? on tumor progression, osteoclastogenesis, and osteoblast differentiation together inhibiting the metastatic potential of the breast cancer cells. Following are the Specific Aims.
Aim 1. To evaluate Ad.sT?RFc and mhTERT Ad.sT?RFc in vitro: Viral replication and sTGF?RIIFc production.
Aim 2. To evaluate sTGF?RIIFc-mediated inhibition of TGF? functions in vitro: TGF? signaling, osteoclastogenesis, and osteoblast differentiation.
Aim 3. To evaluate Ad.sT?RFc and mhTERTAd.sT?RFc in vivo: Virus distribution, replication, gene expression, safety, and toxicity.
Aim 4. To evaluate Ad.sT?RFc and mhTERT Ad.sT?RFc in vivo: Tumor growth, metastasis, and osteolytic bone destruction. Nearly 200, 000 women are diagnosed with breast cancer each year in the United States. Most of the patients with advanced breast cancer develop bone metastases causing considerable morbidity and mortality. Thus, there is an urgent need to develop novel approaches to treat breast cancer. The goal of this project is to develop a new gene therapy method to treat breast cancer. The successful completion of the preclinical research proposed here is essential before clinical trials on breast cancer patients can be initiated.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Arya, Suresh
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northshore University Healthsystem
United States
Zip Code
Xu, W; Neill, T; Yang, Y et al. (2015) The systemic delivery of an oncolytic adenovirus expressing decorin inhibits bone metastasis in a mouse model of human prostate cancer. Gene Ther 22:247-56
Xu, Weidong; Zhang, Zhenwei; Yang, Yuefeng et al. (2014) Ad5/48 hexon oncolytic virus expressing sTGF?RIIFc produces reduced hepatic and systemic toxicities and inhibits prostate cancer bone metastases. Mol Ther 22:1504-1517
Zhang, Z; Hu, Z; Gupta, J et al. (2012) Intravenous administration of adenoviruses targeting transforming growth factor beta signaling inhibits established bone metastases in 4T1 mouse mammary tumor model in an immunocompetent syngeneic host. Cancer Gene Ther 19:630-6
Hu, Zebin; Gerseny, Helen; Zhang, Zhenwei et al. (2011) Oncolytic adenovirus expressing soluble TGF? receptor II-Fc-mediated inhibition of established bone metastases: a safe and effective systemic therapeutic approach for breast cancer. Mol Ther 19:1609-18
Gupta, Janhavi; Robbins, John; Jilling, Tamas et al. (2011) TGFýý-dependent induction of interleukin-11 and interleukin-8 involves SMAD and p38 MAPK pathways in breast tumor models with varied bone metastases potential. Cancer Biol Ther 11:311-6
Zhang, Zhenwei; Krimmel, Jeffrey; Zhang, Zhiling et al. (2011) Systemic delivery of a novel liver-detargeted oncolytic adenovirus causes reduced liver toxicity but maintains the antitumor response in a breast cancer bone metastasis model. Hum Gene Ther 22:1137-42
Hu, Z; Robbins, J S; Pister, A et al. (2010) A modified hTERT promoter-directed oncolytic adenovirus replication with concurrent inhibition of TGFbeta signaling for breast cancer therapy. Cancer Gene Ther 17:235-43
Hu, Zebin; Zhang, Zhenwei; Guise, Theresa et al. (2010) Systemic delivery of an oncolytic adenovirus expressing soluble transforming growth factor-? receptor II-Fc fusion protein can inhibit breast cancer bone metastasis in a mouse model. Hum Gene Ther 21:1623-9
Akhtari, Mojtaba; Mansuri, Junaid; Newman, Kam A et al. (2008) Biology of breast cancer bone metastasis. Cancer Biol Ther 7:3-9